In recent years, significant developments in laser technology have led to its application in the field of ophthalmic surgery. In particular, laser surgery has become the technique of choice for many ophthalmic surgical applications. While a number of common treatments involve purposeful retinal destruction (e.g., laser photocoagulation), other treatments may result in complications including retinal damage (P. L. Prendiville et al., Int. Ophthalmol. Clin. 32:179-204 (1992)). Accidental retinal damage has also been reported in ophthalmic practice (Y. Barkana et al., Surv. Ophthalmol, 44; 459-478 (2000)). In addition, laboratory, industrial and military use of lasers has led to many reported laser-induced eye injuries (H. F. Liu et al., Health. Phys. 56:711-716 (1989)). More recently, laser weapons aimed to damage electro-optical sensors and visually incapacitate soldiers by destroying parts of their retinas have been developed (Y. Barkana et al., 2000).
Retinal damage due to any of the foregoing causes typically triggers a process of secondary degeneration in neuronal cells adjacent to the primary lesion (E. Yoles et al., Exp. Neurol. 153:1-7 (1998)). This process of secondary degeneration starts by the release of noxious compounds from the primary lesion that subsequently spread and damage neighboring cells. The resulting damage to the retina, and corresponding functional consequences, are increased manifold by these secondary degeneration processes. Although there have been advances in the field, here remains a need for methods of treating, and minimizing, these secondary degeneration processes.
NAP, an 8-amino acid peptide (NAPVSIPQ=Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) (SEQ ID NO:2), is derived from a novel protein, activity-dependent neuroprotective protein, ADNP (U.S. Pat. No. 6,613,740; Bassan et al., J. Neurochem. 72: 1283-1293 (1999); Zamostiano, et al., J. Biol. Chem. 276:708-714 (2001)). The NAP sequence within the ADNP gene is identical in rodents and humans (U.S. Pat. No. 6,613,740; Zamostiano, et al., J. Biol. Chem. 276:708-714 (2001)).
In cell cultures, NAP has been shown to have neuroprotective activity on cells of the central nervous system (CNS) at femtomolar concentrations (Bassan et al., 1999; Offen et al., Brain Res. 854:257-262 (2000)). Several animal models have also demonstrated NAP activity on diseases of the CNS. In animal models simulating parts of the Alzheimer's disease pathology, NAP was protective (Bassan et al., 1999; Gozes et al., J. Pharmacol. Exp. Ther. 293:1091-1098 (2000); see also U.S. Pat. No. 6,613,740). In normal aging rats, intranasal administration of NAP improved performance in the Morris water maze (Gozes et al., J. Mol. Neurosci. 19:175-178 (2002). NAP reduced infarct volume and motor unction deficits after ischemic injury, by decreasing apoptosis (Leker et al., Stroke 33:1085-1092 (2002)) and reducing damage caused by closed head injury in mice by decreasing inflammation (Beni Adani et al., J. Pharmacol. Exp. Ther. 296:57-63 (2001); Romano et al., J. Mol. Neurosci. 18:37-45 (2002); Zaltzman et al., NeuroReport 14:481-484 (2003)). NAP has been shown to provide protective intervention in a model of fetal alcohol syndrome, reducing fetal demise and growth restrictions (Spong et. al., J Pharmacol Exp Ther. 297.774-9 (2001)). Additionally, long term nasal NAP application in mice resulted in decreased anxiety (Alcalay et al., Neurosci Lett. 361(1-3):128-31 (2004)).
SAL, a 9-amino acid peptide (SALLRSIPA=Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala) (SEQ ID NO:1), also known as ADNF-9 or ADNF-1, was identified as the shortest active form of ADNF (see U.S. Pat. No. 6,174,862). SAL has been shown in in-vitro assays and in vivo disease models to keep neurons of the central nervous system alive in response to various insults (e.g., Gozes et al., 2000, infra; Brenneman et al., 1998. J. Pharmacol. Exp. Ther. 285, 619-627). D-SAL is an all D-amino acid derivative of SAL that is stable and orally available (Brenneman, el al., J Pharmacol Exp Ther. 309:1190-7 (2004)) and surprisingly exhibits similar biological activity (potency and efficacy) to SAL in the systems tested. ADNF-1 complexes are described in International PCT Application No. PCT/US02/29146, filed Sep. 12, 2002 (published as WO03022226).
ADNF polypeptides, including NAP and SAL, and uses thereof in neuroprotection against disorders of the central nervous system, are the subject of numerous patents and patent applications including International PCT Publication No. WO01/92333, U.S. application Ser. No. 07/871,973 filed Apr. 22, 1992, now U.S. Pat. No. 5,767,240; U.S. application Ser. No. 08/342,297 filed Oct. 17, 1994 (published as WO96/11948), now U.S. Pat. No. 6,174,862; U.S. application Ser. No. 60/037,404 filed Feb. 7, 1997 published as WO98/35042); U.S. application Ser. No. 09/187,330 filed Nov. 11, 1998 (published as WO00/27875); U.S. application Ser. No. 09/267,511 filed Mar. 12, 1999 (published as WO00/53217); U.S. Pat. No. 6,613,740; U.S. application Ser. No. 60/149,956 filed Aug. 18, 1999 (published as WO01/12654); U.S. application Ser. No. 60/208,944 filed May 31, 2000; U.S. application Ser. No. 60/267,805 filed Feb. 8, 2001; International PCT Application No. PCT/IL2004/000232 filed Mar. 11, 2004 (published as WO 2004/080957); and International PCT Application No. PCT/US02/29146, filed Sep. 12, 2002 (published as WO 2003/022226); each of which are incorporated by reference in their entirety.
Given the increased use of lasers, both therapeutically and as weapons, improved methods of treating retinal damage caused by lasers are needed. The present invention solves his and other needs.